Molecular mechanisms of insulin resistance and altered carbohydrate metabolism in PCOS: a scoping review

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting women of reproductive age, characterized by oligo- or anovulation, hyperandrogenism, and polycystic ovarian morphology. Beyond its reproductive manifestations, PCOS is increasingly recognized as a complex endocrine-metabolic disorder frequently associated with impaired carbohydrate metabolism and insulin resistance, often independent of body mass. Despite extensive research, the molecular mechanisms underlying insulin resistance across metabolic and reproductive tissues in PCOS remain incompletely characterized. This scoping review aimed to systematically map molecular disturbances in insulin signaling and carbohydrate metabolism in PCOS, explore associations between tissue-specific mechanisms, and identify key gaps in the current evidence. We included peer-reviewed original studies published in English between January 2018 and May 2025, retrieved from PubMed, Embase, and Web of Science, that investigated molecular or cellular pathways related to insulin resistance or glucose metabolism in PCOS. The available evidence predominantly addressed granulosa cells and ovarian tissue, with additional data from endometrium, liver, adipose tissue, skeletal muscle, pancreatic beta-cells, and systemic regulatory pathways. Recurrent mechanisms underlying insulin resistance in PCOS included post-receptor defects in IRS/PI3K/AKT and MAPK signaling, impaired GLUT4 expression and trafficking, mitochondrial and glycolytic dysfunction, chronic low-grade inflammation, androgen receptor-mediated metabolic reprogramming, circadian rhythm disruption, and epigenetic or environmental modulators. Evidence from human studies remains limited, with many proposed molecular mechanisms being supported predominantly by rodent or cell line models. To translate this knowledge to clinical and therapeutic application, additional high-quality longitudinal human research with comprehensive multi-omics is necessary to validate key mechanisms in ovarian and metabolic tissues, especially those involving IRS/PI3K/AKT signaling, GLUT4 regulation, inflammation, and androgen-driven metabolic dysfunction.